Our laboratory has shown that oxygen tension is an important regulator of the rate of cell division of cardiac muscle cells in vitro and in vivo. In the present study we hope to clarify the molecular mechanism by which oxygen modifies cell proliferation. Oxygen acts probably to alter the redox state of a control substance (e.g., NAD yields NADH). NAD serves as a precursor for poly(ADP-ribose), an inhibitor of DNA, which is involved in cell proliferation and differentiation. We plan to study the participation of poly(ADP-ribose) in oxygen modulated cell proliferation of cardiac myocytes, in oxygen modulated differentiation of skeletal muscle, and in cardiac hypertrophy. We shall purify and characterize physico-chemically poly(ADP-ribose) polymerase, the enzyme that catalyzes the synthesis of poly(ADP-ribose), in adult rat and guinea pig heart. Furthermore, we plan to describe kinetic properties, subunit structure if any, and the presence of possible cardiac isoenzymes. We have shown that poly(ADP-ribose) polymerase in cardiac cells has very different kinetic properties (km, Vmax and pH optimum) when grown in 5% and 20% oxygen. This raises the possible existence of isoenzymes with different functional activity at different oxygen tensions. If the above approaches are successful, we shall apply these techniques later to fetal and newborn myocardial tissue. We shall also identify in tissue culture the period of the cell cycle during which oxygen exerts its effects on growth by calculating DNA distributions using flow cytometric techniques. Lastly, we plan to develop an animal model (probably in guinea pig) in which viable young can be obtained prematurely by Caesarean section. Then, using autoradiographic techniques, we plan to compare rates of division and ultimate number of cardiac muscle cells in adulthood in prematurely delivered animals with controls born at term.